Reactive oxygen intermediates as regulators of TNF-alpha production in rat lung inflammation induced by silica.
Reactive oxygen intermediates as regulators of TNF-alpha production in rat lung inflammation induced by silica.
复制标题
活性氧中间体作为二氧化硅诱导的大鼠肺部炎症中 TNF-α 产生的调节剂。
DOI：
10.4049/jimmunol.156.4.1540
复制
发表时间：
1996
影响因子：
4.4
通讯作者：
B. Pipy
中科院分区：
文献类型：
--
作者：
S. Gossart;C. Cambon;C. Orfila;M. Séguélas;J. Lepert;J. Rami;P. Carré;B. Pipy
接触二氧化硅等矿物粉尘与进行性肺部炎症和纤维化有关。有证据表明，肺泡巨噬细胞（AM）释放活性氧中间体（ROI）和细胞因子与二氧化硅暴露相关的肺损伤有关。然而，人们对这两个调解人之间的时间顺序和关系知之甚少。在这项研究中，使用了矽肺动物模型，允许在支气管肺泡灌洗后同时随访肺组织病理学状态、蛋白质（生物测定）和 mRNA（逆转录酶-PCR）水平的 AM TNF-α 产生以及 ROI（鲁米诺依赖性化学发光）的释放。特别是，已经表明，大鼠气管内滴注二氧化硅（50 mg/kg）会导致纤维化，其特征是细胞间质浸润和肉芽肿，并且在 AM 中，它导致 1) 12-O-十四烷酰佛波醇-13-乙酸酯或酵母聚糖触发的 ROI 产生早期持续增加（第 1、3、14 和 28 天）治疗后），2）第 3 天和第 14 天 TNF-α mRNA 表达和蛋白质分泌增加。自由基清除剂预处理（N-叔丁基-α-苯硝酮）逆转了肺组织病理学变化，并减少了 AM ROI 产生和 mRNA 水平的 TNF-α 表达。这些发现表明 ROI 的产生是决定二氧化硅诱导的炎症过程的重要主要事件。 ROI 可以以自分泌或旁分泌方式起作用，并通过促进基因表达的机制调节 TNF-α 的产生。抗 TNF-α Ab 治疗证实了这种细胞因子在矽肺发病机制中的关键作用。
Exposure to mineral dusts such as silica has been associated with progressive pulmonary inflammation and fibrosis. There is evidence that the release of reactive oxygen intermediates (ROI) and cytokines by alveolar macrophages (AM) is involved in lung injury associated with silica exposure. However, the chronology and relationship between these two mediators are poorly understood. In this study, an animal model of silicosis has been used, allowing simultaneous follow-up of lung histopathologic state, AM TNF-alpha production at the protein (biologic assay) and mRNA (reverse transcriptase-PCR) levels, and the release of ROI (luminol-dependent chemiluminescence), after bronchoalveolar lavages. In particular, it has been shown that intratracheal instillation of silica (50 mg/kg) in rats led to fibrosis characterized by cellular interstitial infiltrates with granulomas, and in AM, it led to 1) an early and continuous increase in 12-O-tetradecanoylphorbol-13-acetate- or zymosan-triggered ROI production (days 1, 3, 14, and 28 post-treatment), and 2) a rise of TNF-alpha mRNA expression and protein secretion on days 3 and 14. A free radical scavenger pretreatment (N-ter-butyl-alpha-phenylnitrone) reversed lung histopathologic changes and decreased AM ROI production and TNF-alpha expression at the level of mRNA. These findings suggest that ROI production is an important primary event determining the silica-induced inflammatory process. ROI may act in an autocrine or paracrine manner and regulate TNF-alpha production by a mechanism promoting gene expression. The critical role of this cytokine in the pathogenesis of silicosis was confirmed by anti-TNF-alpha Ab treatment.